ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.268G>A (p.Gly90Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003803287 SCV004592207 likely pathogenic Dystonia 5; GTP cyclohydrolase I deficiency 2023-06-07 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly90 amino acid residue in GCH1. Other variant(s) that disrupt this residue have been observed in individuals with GCH1-related conditions (PMID: 10076897), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCH1 protein function. This missense change has been observed in individuals with dopa-responsive dystonia (PMID: 29470312). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 90 of the GCH1 protein (p.Gly90Arg).

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